The following research projects are etiologic and human population based and all have various molecular components:SUCCEED directed by Dr. Wentzensen is a cross-sectional study among women referred for abnormal cevrical cancer screening results focused on the identification of biomarkers of risk at each progressive disease stage, aimed to identify the molecular events that are necessary and sufficient for progression to cervical cancer. Frozen specimens, often multiple, from 2,500 women with varying grades of cervical neoplasia (including the ectocervix, transformation zone, and endocervix) have already been collected. In a new study, the Biopsy Study conducted at the same center in Oklahoma, Dr. Wentzensen is investigating the earliest discernible transitions from HPV infection to CIN3 and the best methods for colposcopic detection of CIN3 to improve current cervical cancer prevention strategies.The ALTS clinical trial evaluated management options for women with abnormal cervical cancer screening results and has been completed several years ago. The specimens collected in women with minor cytological abnormalities and 2 year follow up still serve as an important resource to evaluate HPV tests and novel biomarkers, such as viral methylation.In the Triage of HPV-positive women Study, novel biomarkers are evaluated to decide who among HPV+/cytology- women needs referral to colposcopy.The cervical tissue immune markers study aims at evaluating various components of the cellular and humoral immune system across cervical disease stages in HIV-infected populations.The case control study of invasive cervical cancer in four Latin-American countries is an important resource to study sero-epidemiologic markers of cervical cancer risk.In the Intramural to India project, cervical cancers and its precursors are studied among HIV-infected women in India. The goal of the project is to understand the interactions between HIV and HPV at different steps in the disease process from HPV infection to precancer and cancer. Another important goal is to evaluate biomarkers for cervical precancers in HIV-infected women. Currently, there is no widely standardized approach for early detection of cervical precancers in HIV-infected populations and it is not clear whether established and novel biomarkers perform equally in HIV-infected and non-HIV-infected populations. In the Intramural to India project, we will evaluate a wide range of tests and biomarkers to evaluate risk of cervical precancer and to improve cervical cancer prevention efforts in HIV/ AIDS populations.Although HPV is implicated in over 90% of anal cancers, it is unknown if the natural history of HPV-induced anal cancer is similar to that of the cervix. There is currently no accepted method for anal cancer screening; in the absence of a standard and effective screening modality, clinicians often resort to high-resolution anoscopy, a diagnostic procedure akin to colposcopy, and directed biopsies. Anal cancer is rare in the general population but is 100 times commoner among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). The role of HIV in anal HPV natural history is not well understood and it is not clear whether the screening approaches for HIV-positive MSM need to be modified. It is crucial to better understand the natural history of HPV-related anal neoplastic disease among HIV-positive individuals to make informed decisions about secondary prevention of anal cancer. In collaboration with Kaiser Permanente Northern California, we have conducted the Anal Cancer Screening Study (ACSS) to describe the natural history of HPV and evaluate the clinical utility of various screening approaches for anal precancer detection. We have evaluated risk factors for anal HPV infection and anal precancer in this population, studied optimal sampling strategies for anal samples, showed that anal cytology is reproducible and the quality is comparable to cervical cytology, conducted modeling exercises to evaluate attribution of anal precancer to individual HPV genotypes and estimate the HPV vaccine-preventable fraction of anal precancer, and have demonstrated the accuracy and clinical utility of several biomarkers that were previously evaluated in cervical cancer screening, including HPV DNA testing with genotyping, HPV mRNA testing, and p16/Ki-67 cytology.